Quench liquids and washing systems for production of microparticles

Abstract

The present invention provides coacervation methods forming compositions for the sustained release water soluble active agents, including biologically active polypeptides. The invention further relates to the discovery of improved non-aqueous quench liquids and washing systems, which enable a reduction in the amount and concentration of hardening agents such as heptane used to produce microparticles, while providing acceptable product yields and residual solvent levels.

Description

RELATED APPLICATION[0001]This application claims the benefit of U.S. Provisional Application No. 60 / 945,188, filed on Jun. 20, 2007. The entire teaching of the above application is incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Numerous proteins and peptides, collectively referred to herein as polypeptides, exhibit biological activity in vivo and are useful as medicaments. Many illnesses or conditions require maintenance of a sustained level of medicament to provide the most effective prophylactic and / or therapeutic effects. Sustained levels are often achieved by the administration of biologically active polypeptides by frequent subcutaneous injections, which often results in fluctuating levels of medicament and poor patient compliance.[0003]As an alternative, the use of biodegradable materials, such as polymers, encapsulating the medicament can be employed as a sustained delivery system. The use of biodegradable polymers, for example, in the form of microparticle...

AI Technical Summary

Benefits of technology

[0018]This invention relates to coacervation processes for forming compositions for the sustained release of water soluble active agents, including biologically active polypeptides. The invention further relates to the discovery of improved non-aqueous quench liquids and washing systems, which enable a reduction in the amount and concentration of hardening agents such as heptane used to produce microparticles, while providing acceptable product yields and residual solvent levels.

[0037]The use of a sugar in the sustained release compositions of the invention improves the bioavailability of the incorporated biologically active polypeptide, e.g., anti-diabetic or glucoregulatory peptides, and minimizes loss of activity due to instability and / or chemical interactions between the polypeptide and other components contained or used in formulating the sustained release composition, while maintaining an excellent release profile.

[0038]The advantages of the sustained release formulations as described herein include increased patient compliance and acceptance by eliminating the need for repetitive administration, increased therapeutic benefit by eliminating fluctuations in active agent concentration in blood levels by providing a desirable release profile, and a potential lowering of the total amount of biologically active polypeptide necessary to provide a therapeutic benefit by reducing these fluctuations.

Problems solved by technology

Sustained levels are often achieved by the administration of biologically active polypeptides by frequent subcutaneous injections, which often results in fluctuating levels of medicament and poor patient compliance.

On the other hand, water soluble drugs may partially partition into the aqueous phase during the preparation process, resulting in a low encapsulation efficiency.

However, the removal of residual solvents, including halogenated solvents commonly used to dissolve the polymer, from microparticles formed by coacervation can be inefficient.

Efforts to lower residual solvent levels can result in lower microparticle yields due to additional processing, or lower potency due to partial extraction of the active agent during solvent removal.

In addition, coacervation processes known in the art consume large volumes of organic solvents when carried out at a commercial scale.

A major contributor to solvent consumption is the quench step, which typically employs heptane as a hardening solvent.

Moreover, the quantity of microparticles that can be produced in a single batch is often limited by the capacity of the quench tank.

Furthermore, pure heptane does not dissipate static charge well, which may present a fire hazard.

Because the processes disclosed in U.S. Pat. Nos. 5,792,477 and 5,916,598 use an aqueous washing system to reduce solvent levels, it suffers from the drawback that it may result in unacceptable depletion of water soluble active agents, such as peptides, from the microparticles.

While U.S. Pat. No. 6,824,822 teaches preferred solvent blends made up of from 50% heptane and 50% ethanol to 95% heptane and 5% ethanol, microspheres quenched with a blend of 50% heptane and 50% ethanol and washed with 100% heptane had unacceptable handling characteristics.

No commercially successful processes are disclosed wherein a coacervate is extracted with a quench liquid containing more than 10% ethanol by weight.

As a result, the process consumes large quantities of heptane.

Moreover, both liquids dissipate static charge poorly.

In addition, the batch size of microparticles is limited by the capacity of the quench tank.

These processes either employ aqueous washing systems, which can result in depletion of water-soluble active agents; or single or multiple step non-aqueous quench and wash steps that employ large quantities of 100% heptane or blends of heptane and an alcohol that comprise at least 90% heptane by weight.

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